ABSTRACT Duchenne muscular dystrophy is an X-linked genetic disorder that begets debilitating health consequences. Most affected patients do not live past their early adulthood primarily due to respiratory complications (e.g., decreased breathing, pneumonia and atelectasis) caused by deterioration of the diaphragm muscle. Current respiratory care therapies, such as mechanically assisted ventilation, remain palliative, and an effective therapeutic strategy targeting the diaphragm muscle to restore the respiratory capacity is a critical need. The objective of this project is to develop a biomaterial-mediated strategy to deliver and engraft muscle satellite cells to the diaphragm to reinstate the respiratory function through restoration of dystrophin, excitation-contraction coupling, and mechanical stability. This objective will be achieved by (1) engineering a synthetic biomaterial that is capable of maintaining and directing muscle satellite cell function in 3D and (2) delivering satellite cells encapsulated in the engineered biomaterial to stimulate engraftment of donor cells, thereby rescuing dystrophin expression, neuromuscular junction formation, and contractile function of the dystrophic diaphragm of young (2 months) and aged (12 months) mdx/mTR mice. The central hypothesis guiding this project is that the engineered niche- containing biomaterial designed to increase satellite cell adhesion, survival, proliferation, and differentiation will enable precise delivery of cells to the inferior surface of the diaphragm, enhance subsequent local cell retention, survival, expansion, migration, and engraftment of the donor cells, and further provide mechanical support to the aged/atrophied dystrophic diaphragm. The outcomes of this work will be significant in advancing the respiratory treatment strategy in the context of Duchenne muscular dystrophy. Salvaging the failing diaphragm muscle, and thereby the respiratory function, will positively impact patients healthspan and quality of life by providing opportunities to bypass the need for mechanically assisted ventilation. Successful completion of this work will also provide an opportunity to further synergize this platform with induced pluripotent stem cells and emergent gene editing technologies to treat diseased diaphragm function of patients suffering from various forms of neuromuscular diseases.